Late‐Stage Modification of Oligopeptides by Nickel‐Catalyzed Stereoselective Radical Addition to Dehydroalanine

Abstract Radical addition to dehydroalanine (Dha) represents an appealing, modular strategy to access non‐canonical peptide analogues for drug discovery. Prior studies on radical addition to the Dha residue of peptides and proteins have demonstrated outstanding functional group compatibility, but the lack of stereoselectivity has limited the synthetic utility of this approach. Herein, we address this challenge by employing chiral nickel catalysts to control the stereoselectivity of radical addition to Dha on oligopeptides. The conditions accommodate a variety of primary and secondary electrophiles to introduce polyethylene glycol, biotin, halo‐tag, and hydrophobic and hydrophilic side chains to the peptide. The reaction features catalyst control to largely override substrate‐based control of stereochemical outcome for modification of short peptides. We anticipate that the discovery of chiral nickel complexes that confer catalyst control will allow rapid, late‐stage modification of peptides featuring nonnatural sidechains.